Effects of glucagon-like peptide-1 (GLP-1) on the heart have been recently recognized, but little is known regarding the cardiovascular physiology of this incretin hormone. GLP-1 can drive myocardial glucose uptake, and has beneficial effects on cardiac function and protection against myocardial ischemic injury in animal models. These effects have been reported for intact GLP-1, acting via the classical GLP-1 receptor, and the degradation product GLP-1 (9-36), which appears to act independent of the GLP-1 receptor. In studies of the effects of obesity and diabetes on myocardial GLP-1 responses, we have produced the first evidence for impaired myocardial GLP-1 responses in the setting of the obese-metabolic syndrome (MetS) in swine and type 2 diabetes mellitus in humans. Based on our preliminary findings we propose to examine the central hypothesis that obesity/MetS attenuates the cardio-metabolic effects of GLP-1 via alterations in parameters of GLP-1 signaling and/or fuel transport regulation. To accomplish our goal, we will examine the following set of Specific Aims: Aim 1 will determine the myocardial effects of GLP-1 in vivo in lean and obese/MetS Ossabaw swine that possess key clinical features of this syndrome, including obesity, insulin resistance/impaired glucose tolerance, dyslipidemia, and hypertension. These studies involve triple tracer PET approaches to measure basal and GLP-1 stimulated myocardial perfusion, total oxidation rate, and substrate utilization rates as well as quantificatin of the effects of GLP-1 on cardiac function, coronary blood flow and substrate metabolism during exercise-induced increases in myocardial metabolism in conscious, instrumented swine. Aim 2 will dissect molecular mechanisms of the impaired myocardial GLP-1 responses in obesity/MetS. We propose to quantify coronary and myocardial GLP-1 receptor expression and assess the effects of GLP-1 and GLP-1(9-36) on the activity of key GLP-1 signaling effectors (e.g. cAMP, PKA, p38 MAPK) and the regulation of myocardial glucose and fatty acid transporters (e.g. GLUT4, FAT/CD36) in lean vs. obese/MetS swine. Aim 3 will examine the cardioprotective effects of GLP-1 in obese/MetS heart following ischemia/reperfusion injury. We propose to quantify the effects of GLP-1 and GLP-1(9-36) on myocardial perfusion, substrate and oxidative metabolism, contractile function and infarct size. Effects of GLP-1 on key signal transduction, markers of myocellular injury, and activation of post-conditioning protective pathways and myocardial injury responses in ischemic and non-ischemic myocardium will also be determined. Data from these integrative/translational studies will provide novel mechanistic insight into the cardiovascular actions of GLP-1 that will significantly advance our understanding of the cardioprotective actions of this incretin hormone. Further, these studies will accelerate discovery of new therapeutic targets or strategies that could substantially improve the cardioprotective efficacy of GLP-1 based therapies in patients with obesity-related cardiovascular disease.